Maedi-Visna Virus

Overview and Taxonomy of Maedi-Visna Virus

Maedi-visna virus (MVV) represents a prototypical member of the Lentivirus genus within the family Retroviridae, subfamily Orthoretrovirinae, and constitutes, together with the caprine arthritis-encephalitis virus (CAEV), the group of pathogens formally designated as small ruminant lentiviruses (SRLVs) [16]. The nomenclature itself is etymologically informative, deriving from the Icelandic terms "maedi" (dyspnea) and "visna" (wasting or atrophy), reflecting the two most historically recognized clinical manifestations: a progressive interstitial pneumonia and a chronic demyelinating encephalomyelitis [16, 21]. The virus was first identified and characterized in Iceland during the mid-20th century following the introduction of apparently healthy Karakul sheep, an episode that remains a seminal case study in the emergence of exotic livestock diseases. Since those initial descriptions, MVV has been documented across virtually all sheep-rearing continents, underscoring its status as a globally endemic pathogen with profound implications for animal health, welfare, and agricultural economics [1, 2, 10, 18].

Taxonomically, MVV is classified under the genus Lentivirus, a group characterized by slow, chronic disease progression, lifelong persistence in the host, and a complex genomic organization that includes canonical retroviral structural genes (gag, pol, env) as well as several accessory genes, most notably vif and rev [16, 21]. The genomic organization of MVV is typical of complex retroviruses. The gag gene encodes the matrix (MA), capsid (CA, p28/p25), and nucleocapsid (NC) proteins, which are essential for virion assembly and structural integrity. The pol gene encodes the viral enzymes: protease (PR), reverse transcriptase (RT), and integrase (IN). The env gene encodes the surface (SU, gp135) and transmembrane (TM, gp46) envelope glycoproteins, which are critical for receptor recognition and viral entry [5, 16]. A hallmark of SRLV biology is the extraordinary degree of genetic heterogeneity, particularly within the env gene, which is a consequence of the error-prone nature of the viral reverse transcriptase and the high rate of recombination during replication [3, 11, 12, 16]. This genetic variability poses substantial challenges for diagnostic test development, vaccine design, and the implementation of effective control programs, as assays developed against one viral strain may demonstrate reduced sensitivity against divergent circulating strains in different geographic regions [3, 9, 28].

MVV is classified phylogenetically into distinct genotypes, with genotype A being the most widely distributed globally and the one most commonly associated with classical maedi-visna disease in sheep [12, 20]. Genotype A itself is further subdivided into subtypes, with strains belonging to subtype A2 appearing particularly prevalent in North America and parts of Asia. For instance, whole-genome sequencing of Chinese MVV isolates, including the NM strain from Inner Mongolia, has unequivocally placed them within the A2 clade, sharing 77.1–86.8% homology in gag and 67.7–75.5% homology in env with reference strains from the United States [12, 20]. These sequence analyses reveal that the surface unit of the envelope glycoprotein (SU5) contains a C-terminal domain with a highly variable motif and distinct amino acid insertions, particularly in variable region 4 (V4), further distinguishing regional strains [12]. More recently, molecular characterization of strains circulating in Germany has also identified genotype B (traditionally associated with CAEV in goats) in sheep, suggesting that interspecies transmission and the co-circulation of multiple SRLV genotypes within a single ovine population may be more common than previously appreciated [19]. This genetic fluidity complicates serological surveillance, as commercially available enzyme-linked immunosorbent assays (ELISAs), which typically rely on recombinant p25 capsid or gp135 envelope antigens, may fail to detect antibodies against divergent viral variants, leading to false-negative results and underestimated prevalence rates [3, 9, 28]. The genetic classification of circulating strains, therefore, is not merely an academic exercise; it is a prerequisite for the rational design of region-specific diagnostic tools and for understanding transmission dynamics at the population level.

From a global epidemiological perspective, MVV infection is enzootic in most countries with significant sheep populations, with reported seroprevalences ranging from less than 2% in regions with rigorous control programs or low-density pastoral systems to over 80% in intensively managed dairy flocks [1, 13, 24]. The World Organisation for Animal Health (WOAH) recognizes MVV as a pathogen of socioeconomic importance, particularly for its insidious impact on flock productivity through reduced milk yield, impaired growth rates, increased mortality, and premature culling. The virus is not considered zoonotic, and the WOAH does not classify it as a notifiable disease requiring immediate international reporting in the same manner as foot-and-mouth disease or peste des petits ruminants; however, its presence creates significant trade barriers for live animals and genetic material, and many countries operate voluntary or mandatory eradication programs to maintain national or regional freedom from infection. A systematic synthesis of available prevalence data illustrates a highly heterogeneous distribution. In Turkey, a recent large-scale serosurvey of Kangal Akkaraman sheep in the Sivas region using commercial ELISA revealed an alarming overall seroprevalence of 49.6% (228/460), with district-level variation from 13.04% to 82.60%, indicating extreme local differences in infection pressure and management practices [1]. Similarly, in southern Croatia, seroprevalence reached 19.02% in Istria County, with the Istrian Pramenka breed disproportionately affected (22.97% seropositivity), whereas nearly zero prevalence was observed in the Pag and Krk island breeds, suggesting a strong association between geographic isolation, breed genetics, and infection risk [10]. In the Mediterranean basin, intensive dairy sheep systems in Greece have reported point seroprevalences as high as 96% on individual farms, with a two-year prospective study demonstrating that horizontal transmission within the barn environment is the dominant driver of new infections, rather than maternal transmission alone [24].

Conversely, lower seroprevalences are frequently observed in less intensively managed populations. In Algeria, the first national serosurvey of 1,400 sheep reported an overall prevalence of only 9.07%, with significant disparities favoring females (20.44%) over males (3.68%), likely reflecting the prolonged retention of ewes within breeding herds and their repeated exposure during parturition and lactation [2]. In Ethiopia, a cross-sectional study in the eastern Amhara region found only 3.24% seropositivity among 494 sheep, although the authors incriminated the introduction of Awassi crossbreeds from a central distributor farm as the primary source of incursion [15]. In Brazil, seroprevalence ranges from 1.4% in Paraná state to 8.2% in the Western Amazon, with the Agar Gel Immunodiffusion (AGID) test being used in many of these earlier studies, which is known to have lower sensitivity compared to modern ELISAs [8, 17]. The introduction of MVV into previously free or low-prevalence regions is almost invariably linked to the importation of live animals. This is starkly demonstrated by the reappearance of MVV in Norway in 2019 after an apparent 14-year absence, where genetic analysis confirmed persistence of the virus within the sheep population since 2005, likely maintained subclinically and evading detection by the prevailing surveillance system [3, 9].

The biological and clinical relevance of MVV infection is inextricably linked to its classification as a lentivirus with a tropism for cells of the monocyte/macrophage lineage. Following initial infection, typically via the respiratory or digestive tract, the virus establishes a persistent, life-long infection characterized by a prolonged asymptomatic phase that can last months to years. The virus replicates primarily in macrophages and dendritic cells, with integration of proviral DNA into the host genome ensuring lifelong carriage [4, 16, 29]. The progressive clinical syndromes arise from a chronic, dysregulated inflammatory response driven by the infected macrophages and the subsequent infiltration of lymphocytes and other inflammatory cells into target organs, including the lungs (interstitial pneumonia, or "maedi"), the udder (indurative mastitis), the joints (arthritis), and the central nervous system (demyelinating encephalitis, or "visna") [4, 7, 16, 27, 29]. The mammary form, in particular, is often underdiagnosed but represents a major economic threat, as subclinical mastitis with progressive fibrosis and atrophy of the glandular parenchyma leads to reduced milk yield and altered milk composition, including increased somatic cell counts and impaired coagulation properties [7, 14, 23]. The virus has been detected in numerous tissues beyond the classical target organs, including in the mesenteric lymph nodes and the epididymis, illustrating that the infection is truly systemic and that viral reservoirs are disseminated throughout the lymphoid system [25, 30].

The genetic determinants of host susceptibility to MVV, and thus a significant component of its taxonomy at the host-pathogen interface, have been mapped to the ovine transmembrane protein 154 gene (TMEM154). This locus has emerged as a major candidate gene influencing resistance or susceptibility to SRLV infection across multiple breeds and geographic regions [6, 19, 22, 26]. The most extensively studied polymorphism is a non-synonymous single nucleotide polymorphism (SNP) resulting in a substitution of glutamic acid (E) with lysine (K) at codon 35 of exon 2. Homozygosity for the protective K allele (KK genotype) is strongly associated with resistance to infection and, in some instances, with the apparent clearance of virus from the circulation. In a longitudinal study of naturally infected rams, the single animal homozygous for the K allele maintained persistently low proviral and viral RNA loads and ultimately became seronegative and PCR-negative, suggesting that this genotype may confer the ability to achieve sterilizing immunity or at least functional cure [26]. In contrast, animals carrying one or two copies of the ancestral E35 allele are at significantly increased risk of seroconversion and viral persistence [6, 22]. A serosurvey of Valle del Belìce sheep in Sicily found that no animal with the KK genotype was seropositive, whereas seroprevalence among EE homozygous animals was substantial [6]. Similarly, among German Pomeranian Coarsewool Sheep, seroprevalence was significantly lower in sheep exclusively carrying the K allele at codon 35 and/or the M allele at codon 44 [19]. The association is not absolute; some animals with the putative susceptible genotype remain seronegative, and vice versa, indicating that additional host genes, viral strain virulence, and environmental factors also contribute to the infection outcome. Nevertheless, the discovery of TMEM154 has opened the door to marker-assisted selection as a complementary strategy to test-and-cull programs for reducing the prevalence of MVV in affected flocks [22, 26].

Molecular Pathogenesis and Viral Replication of MVV

Maedi-Visna virus (MVV), a member of the Lentivirus genus within the Retroviridae family, establishes a lifelong, persistent infection in sheep, characterized by a remarkably protracted clinical latency followed by progressive, chronic inflammatory disease [16, 21]. The molecular pathogenesis of MVV is inextricably linked to its unique replicative strategy, its sophisticated arsenal for subverting host immune defenses, and the complex interplay between viral genetics and host susceptibility factors. Unlike the more cytopathic lentiviruses, MVV has evolved a paradigm of "slow" replication that is exquisitely adapted to its monocyte/macrophage target cell, enabling the virus to evade clearance while gradually inducing the immunopathological lesions that define the disease.

Viral Entry, Cellular Tropism, and the Establishment of Proviral Latency

The MVV lifecycle is fundamentally governed by its tropism for cells of the monocyte/macrophage lineage. Infection is initiated when the viral envelope glycoprotein (Env), composed of the surface (SU) and transmembrane (TM) subunits, engages a cognate receptor on the host cell [5, 16]. While the specific receptor for MVV has not been definitively identified with the same precision as CD4 for HIV-1, the available evidence strongly points to a receptor that is expressed selectively on macrophages and dendritic cells. Critically, the virus does not productively infect circulating blood monocytes. Instead, proviral DNA integrates into the host genome of these precursor cells, where it remains transcriptionally silent. This is the central tenet of MVV’s pathogenesis: latency is maintained during the monocyte’s circulatory phase. Viral replication is strictly linked to cellular differentiation. Only when the monocyte migrates into tissues and differentiates into a mature, activated macrophage does the cellular environment become permissive for proviral transcription and the production of new virions [16]. This differentiation-dependent replication cycle is the primary mechanism that allows MVV to establish a persistent, life-long infection while effectively hiding from the initial adaptive immune response. Studies utilizing immunohistochemistry have consistently demonstrated the presence of MVV p28 capsid antigen within macrophages and dendritic cells in a range of affected tissues, including the lungs, mammary glands, lymph nodes, and joints, confirming these cells as the primary viral reservoirs in vivo [4, 7, 23, 29, 35].

The long terminal repeat (LTR) region of the MVV genome contains the critical regulatory elements that control this differentiation-dependent transcription. The LTR acts as a molecular switch, whose activity is modulated by cellular transcription factors that change in abundance or activity as the monocyte differentiates into a macrophage [11, 32, 37]. This mechanism ensures that viral gene expression is tightly coupled to the cellular activation state of the host cell, a strategy that contrasts sharply with the more promiscuous replication of some other retroviruses.

The Vif Protein: A Master Adaptor for Host Immune Evasion

At the forefront of MVV’s molecular countermeasures is the viral infectivity factor (Vif). Like other lentiviruses, MVV must neutralize the potent antiviral activity of the host’s apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of cytidine deaminases, particularly ovine A3Z2-Z3 (oaA3Z2-Z3) [33, 36, 38]. These host restriction factors are lethal to the virus; if packaged into progeny virions, they hypermutate the nascent viral DNA during reverse transcription, rendering the provirus non-functional. The canonical function of Vif is to prevent this by targeting APOBEC3 proteins for proteasomal degradation, a task it accomplishes by acting as a molecular adaptor [34, 36].

The molecular architecture of MVV Vif is both conserved and uniquely adapted. It recruits a host Cullin-RING E3 ubiquitin ligase complex, specifically the Cul5-EloB-EloC complex, to ubiquitinate oaA3Z2-Z3, marking it for destruction by the proteasome [38]. However, a pivotal distinction exists between MVV Vif and its lentiviral counterparts, such as HIV-1 Vif. While HIV-1 Vif requires the non-canonical cofactor CBFβ (core-binding factor subunit beta) to stabilize this E3 ligase complex, MVV Vif has evolved to hijack an entirely different host protein: Cyclophilin A (CypA) [33, 36]. High-resolution cryo-electron microscopy structures of the MVV Vif-CypA-E3 ligase complex have revealed the intricate details of this specific interaction, demonstrating how MVV Vif forms a unique, non-canonical interface to capture CypA and use it as a scaffold to promote the degradation of the antiviral APOBEC3 enzymes [33]. This structural and functional divergence underscores a remarkable evolutionary adaptation, illustrating how MVV has solved a universal lentiviral problem, counteracting APOBEC3, by commandeering a different host cellular machine from that used by primate lentiviruses [33, 36].

Beyond its role in APOBEC3 degradation, recent research has uncovered a conserved, non-canonical function of MVV Vif that is central to its pathogenesis. It has been demonstrated that MVV Vif efficiently targets and degrades all five members of the B56 family of regulatory subunits of protein phosphatase 2A (PP2A), a master regulator of the host phosphoproteome [34]. This Vif-mediated depletion of B56 proteins has a dramatic downstream effect: it forces the host cell to arrest at the G2/M checkpoint of the cell cycle [34]. While the induction of G2/M arrest is a known consequence of HIV-1 Vif activity, its discovery in MVV Vif indicates that this is an ancient and conserved function of lentiviral Vif proteins [34]. The biological advantage this confers to the virus is likely multifaceted. By arresting the macrophage cell cycle, MVV may create an optimal environment for its own replication, potentially by increasing the availability of cellular cofactors or by suppressing the expression of other antiviral factors.

Genetic Variability, Quasispecies, and Viral Evolution

MVV is characterized by exceptionally high genetic heterogeneity, a trait common to RNA viruses that lack proofreading capacity. This is a direct consequence of the error-prone nature of reverse transcriptase and the high rate of recombination during replication. The viral genome, approximately 9.2 kilobases in length, exhibits significant variability, with the env gene being the most hypervariable region [12]. Sequence homology between different MVV isolates can be as low as 67.7% for env and 77.1% for the more conserved gag gene [12]. This genetic diversity manifests as a quasispecies swarm within a single infected host, allowing the virus to rapidly adapt to selective pressures, such as the host immune response or the constraints imposed by diagnostic tests.

Phylogenetic analysis has classified MVV strains into several genotypes, with genotype A (particularly A2 and A3) being the most widespread and commonly isolated globally, including in strains from the United States, China, and Europe [12, 19, 20]. This classification is crucial for understanding global epidemiology and for designing diagnostic tools that are capable of detecting the diverse array of circulating strains. The high variability in the env gene, which encodes the surface glycoprotein (SU5), is a significant driver of antigenic variation, enabling the virus to continuously evade neutralizing antibody responses. Studies have identified a highly variable motif at the C-terminus of SU5, as well as amino acid insertions in variable region 4, which likely contribute to this immune evasion [12]. Furthermore, the genetic variability of MVV has direct implications for molecular diagnostics; the use of primers targeting conserved regions like the gag and pol genes is essential, but even these must be carefully selected to ensure broad detection across strains. Primers targeting the LTR region, often the most conserved part of the genome, may offer superior sensitivity for detecting a wider range of variants [37].

Host Genetic Determinants of Susceptibility: The Central Role of TMEM154

The interaction between MVV and its host is not one-sided; the host genome plays a decisive role in determining susceptibility to infection and the rate of disease progression. The most significant host genetic determinant identified to date is the transmembrane protein 154 gene (TMEM154) [6, 22, 26]. This gene encodes a protein whose function is not fully elucidated, but a specific single nucleotide polymorphism (SNP) in exon 2, resulting in a glutamate (E) to lysine (K) substitution at codon 35 (E35K), has been strongly and consistently associated with resistance to MVV infection [6, 19, 22, 26].

Epidemiological studies across diverse breeds and geographic regions, from Turkish sheep to Pomeranian Coarsewool Sheep in Germany and Valle del Belìce sheep in Sicily, have confirmed this association [6, 19, 22]. Homozygous animals carrying two copies of the protective 'K' allele (KK genotype) are substantially less likely to seroconvert and, if infected, maintain significantly lower proviral loads [6, 26]. In some cases, KK homozygous rams have demonstrated the ability to clear the infection to below detectable limits over time, suggesting that this genotype not only reduces susceptibility but may also promote viral clearance [26]. In contrast, animals with one or two copies of the susceptible 'E' allele (EE or EK genotypes), which is more common in many breeds, show a higher risk of infection, higher seroprevalence, and higher viral loads [6, 19, 22]. The risk of infection can be three-fold higher for ewes carrying the susceptible E35 haplotype [22]. This genetic marker represents one of the most compelling targets for selective breeding programs aimed at enhancing resistance to MVV, offering a path toward genetic control of the disease at the flock level [6, 22].

The Molecular Basis of Immunopathology: Dysregulated Inflammation and Lesion Formation

The clinical manifestations of MVV, progressive interstitial pneumonia, indurative mastitis, arthritis, and encephalitis, are not caused by direct virus-induced cytolysis. Instead, they are the result of a chronic, dysregulated, and ultimately destructive host inflammatory immune response [16, 35]. The virus, through its persistent replication in differentiated macrophages, creates a perpetual source of antigenic stimulation that drives an exaggerated and poorly controlled immune reaction.

Transcriptomic analysis of lung tissues from MVV-infected sheep has provided deep insights into this molecular pathogenesis. Infection triggers the differential expression of thousands of genes, with a profound upregulation of genes encoding chemokines and cytokines that orchestrate the recruitment and activation of immune cells [31]. A massive influx of CD4+ and CD8+ T lymphocytes, B cells, and macrophages into the affected tissue is the hallmark of the disease [31, 35]. The gene expression profile is dominated by molecules that promote this cellular infiltration and activation. For example, multiple CXC chemokines, including CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, and CXCL13, are significantly upregulated [31]. These molecules are potent chemoattractants for T cells, B cells, and macrophages, explaining the perivascular and interstitial lymphoid aggregates characteristic of MVV pathology. Similarly, the upregulation of CCL2, matrix metalloproteinase 9 (MMP9), and interferon-gamma (IFN-γ) indicates a T-helper 1 (Th1)-biased inflammatory response that is effective at recruiting cells but ultimately leads to tissue destruction and fibrosis [31, 35].

Remarkably, while these pro-inflammatory signals are induced, there is also evidence of immune dysfunction. Analysis of cytokine expression in naturally infected animals has revealed a downregulation of multiple key cytokines, including IL-10, IFN-γ, TNFα, IL-4, IL-2, and IL-6 in many cases [35]. This paradoxical suppression of the very cytokines that mediate antiviral immunity may contribute to the failure of the host to clear the virus and likely promotes the establishment of a persistent, smoldering infection. This complex and partially contradictory transcriptional profile, simultaneously driving inflammation while suppressing certain immune pathways, highlights the sophisticated way in which MVV manipulates the host response to its own advantage, creating a microenvironment that is both inflammatory and permissive for viral persistence. The resulting lesion in the lungs is a severe, lymphoproliferative interstitial pneumonia, and in the mammary gland, it manifests as a lymphocytic interstitial mastitis that leads to atrophy of glandular tissue and fibrosis [7].

Global and Regional Epidemiology of MVV Infection

Maedi-Visna virus (MVV), a prototypical small ruminant lentivirus (SRLV), exhibits a truly global distribution, having been documented in sheep populations across six continents. The epidemiology of MVV infection is characterized by profound heterogeneity, with seroprevalence rates ranging from less than 1% in certain intensively managed populations to over 80% in endemic flocks. This variability is not stochastic but rather reflects a complex interplay of viral genetic diversity, host genetic susceptibility, management practices, climatic conditions, and the diagnostic modalities employed for surveillance. Understanding this intricate epidemiological landscape is paramount for designing effective, region-specific control programs, as the World Organisation for Animal Health (WOAH) recognizes the significant economic burden imposed by SRLV infections on global small ruminant production systems.

Global Seroprevalence Patterns and Continental Disparities

The global burden of MVV infection is substantial, yet precise estimates remain elusive due to the lack of standardized surveillance in many regions. Early serological surveys, primarily utilizing agar gel immunodiffusion (AGID) tests, likely underestimated true prevalence due to the test's lower sensitivity compared to modern enzyme-linked immunosorbent assays (ELISAs). Contemporary data, leveraging more sensitive indirect ELISAs, reveal a stark picture of widespread endemicity.

In Europe, where MVV was first recognized in the 1930s in South Africa and subsequently described in Iceland, the virus is entrenched in many national sheep populations. A landmark study in Sardinia, Italy, involving over 1,000 Sarda dairy ewes, reported an individual animal seroprevalence of 43.6%, with only one of 23 farms being completely free of infection [14]. This highlights the intense viral circulation within intensive Mediterranean dairy systems. Similarly, a two-year prospective study in Greece on intensively reared Chios and Lacaune ewes revealed a staggering period seroprevalence of 84.8%, with an incidence rate of 33.6 new cases per 100 sheep-semesters, underscoring the rapidity of horizontal transmission under confined housing conditions [24]. In Croatia, a cross-sectional study in three southwestern counties found an overall seroprevalence of 10.0%, but with significant regional variation, reaching 19.02% in Istria County compared to just 1.07% in Primorje-Gorski Kotar County [10]. This geographic clustering is a hallmark of MVV epidemiology. In Germany, a recent study of the native Pomeranian Coarsewool Sheep breed found a lower individual seroprevalence of 3.5%, yet 17.1% of flocks were affected, with within-flock prevalence ranging from 5.3% to 37.5% [19]. A study in Romania investigating coinfection with Jaagsiekte sheep retrovirus found that 47.6% of sheep with pulmonary adenomatosis were also positive for MVV, indicating a high co-circulation rate in that population [44]. In Turkey, seroprevalence varies dramatically by region and breed. A large-scale study of 2,266 ewes across 11 flocks reported within-flock seroprevalence ranging from 2% to 83% [22]. A focused study in the Sivas region on Kangal Akkaraman sheep found an overall seroprevalence of 49.6%, with district-level rates varying from 13.04% to 82.60% [1]. Conversely, a study in the Yozgat region reported a lower seroprevalence of 6.25% in sheep [43], while a study in Van province found 10.5% seropositivity [45]. These data from Turkey alone illustrate the profound micro-epidemiological variation that exists even within a single country.

In the Americas, the epidemiological picture is equally complex. In the United States, MVV (often referred to as ovine progressive pneumonia virus) is endemic, with herd-level prevalence often exceeding 30-40% in many regions, though national surveillance data are limited. In Brazil, seroprevalence is highly variable. A study in the state of Paraná found a very low individual prevalence of 1.4% using the less sensitive AGID test [8], while a study in the Western Amazon (Acre) found 8.2% seropositivity [17]. In the state of Maranhão, a prevalence of 2.02% was reported [27]. However, a study in Santa Catarina confirmed the presence of the virus via PCR in animals with typical clinical signs, demonstrating that even low seroprevalence can mask significant clinical disease [47]. These Brazilian data suggest that MVV is widely distributed but often at lower within-flock levels compared to European intensive systems, likely due to more extensive management practices.

In Africa, data are sparse but revealing. The first national seroprevalence survey in Algeria reported an overall seroprevalence of 9.07% among 1,400 sheep, with significant regional variation (Central region: 3.36% vs. East: 0.86%) and a striking sex disparity (females: 20.44% vs. males: 3.68%) [2]. In Ethiopia, studies have reported seroprevalences ranging from 3.24% in the eastern Amhara region [15] to 8.15% in the North Shewa Zone [40]. The Ethiopian data highlight the role of imported breeds, such as the Awassi cross, as potential sources of introduction into local flocks [15].

In Asia, MVV is increasingly recognized as a significant pathogen. In China, the virus has been present for decades, with molecular characterization of strains from Inner Mongolia revealing they belong to genotype A2, closely related to US isolates [12, 20]. A study in Inner Mongolia found concurrent infection with JSRV and MVV in 0.94% of slaughtered rams, confirming the presence of the virus in commercial flocks [39]. In India, a comprehensive study of 701 biological samples from sheep and goats detected MVV nucleic acid in 10.41% of samples, with seroprevalence of 22.9% in sheep and 15.59% in goats [35]. Another Indian study found MVV nucleic acid in 10.7% of 657 samples, with the highest positivity in lung tissues (25.7%) [4]. In Iraq, molecular detection in Awassi sheep revealed a prevalence of 12.85% [11], while a serological study in Nineveh province found a higher rate of 22.9% using ELISA [41]. In Japan, the virus was first isolated in 2011 from asymptomatic sheep, confirming its presence in the country [46]. In Turkey, a study in the Şanlıurfa region using AGID on 1,096 sheep found evidence of infection, though specific prevalence was not detailed [42].

Regional Risk Factors and Transmission Dynamics

The profound regional variation in MVV seroprevalence is not random but is driven by identifiable risk factors that operate at the animal, flock, and regional levels. The most consistently identified risk factor across multiple studies is management intensity, particularly housing. A seminal epidemiological modeling study demonstrated that transmission rates amongst housed sheep are approximately 1,000 times faster than when sheep are at pasture, where transmission is negligible [13]. The same study concluded that MV is overwhelmingly a disease of housing, where close contact facilitates the respiratory and aerosol transmission that is the primary route of horizontal spread. This is corroborated by field data from Greece, where intensive dairy systems showed an 84.8% seroprevalence [24], and from Italy, where similar systems showed 43.6% prevalence [14]. In contrast, studies from Brazil, where extensive grazing is common, report much lower seroprevalences (1.4-8.2%) [8, 17, 27].

Geographic location itself is a powerful risk factor, often serving as a proxy for management practices, breed composition, and historical introduction of the virus. In Croatia, sheep in Istria County had a 4.77 times higher odds of seropositivity compared to those in other counties [10]. In Turkey, the White Karaman-Kangal breed was found to be 18 times more likely to be infected than other breeds in one study [48], while in the Sivas region, seroprevalence ranged from 13% to 83% across different districts [1]. In Algeria, the Central region had a significantly higher seroprevalence (3.36%) than the East (0.86%) [2]. These geographic patterns likely reflect historical trade routes, the introduction of infected stock, and regional differences in flock management.

Breed is a complex and often confounded risk factor. While some studies report significant breed-associated differences, these may be due to management rather than true genetic susceptibility. In Croatia, Istrian Pramenka and Jezersko-Solcava sheep had significantly higher seroprevalence (22.97% and 23.53%, respectively) than other breeds [10]. In Brazil, White Dorper sheep showed a 33.33% seroprevalence compared to 1.66% in Dorper and 1.67% in Santa Inês [27]. However, when management is controlled, breed effects often diminish. The most compelling evidence for a genetic component comes from studies on the TMEM154 gene. A major candidate gene for susceptibility, the TMEM154 E35K polymorphism has been consistently associated with infection risk. In Turkish sheep, ewes with one or two copies of the highly-susceptible E35 haplotype had a 3-fold greater risk of infection compared to those with the protective K35 allele [22]. In the Valle del Belìce breed in Sicily, no individuals with the resistant KK genotype were seropositive [6]. Critically, a longitudinal study in the UK demonstrated that a ram homozygous for the K allele cleared infection to below detectable limits over 16 months, providing direct evidence of a functional resistance mechanism [26]. In German Pomeranian Coarsewool Sheep, sheep carrying the K allele at codon 35 and/or the M allele at codon 44 had significantly lower seroprevalence [19]. These findings have profound implications for selective breeding programs aimed at reducing population-level susceptibility.

Age is a near-universal risk factor, with seroprevalence increasing progressively with age. This reflects the cumulative probability of exposure over time in an endemic setting. In the Sivas region of Turkey, seropositivity increased from 30% in younger animals to over 50% in older age groups [1]. In Algeria, seroprevalence peaked in the 1-5 year age group (10.43%) [2]. In Germany, sheep older than 3 years showed the highest seroprevalence [19]. This age-related increase is a classic epidemiological pattern for a persistent, lifelong infection with a long incubation period.

Sex is a variable risk factor, with most studies reporting higher seroprevalence in females. In Algeria, females had a 20.44% seroprevalence compared to 3.68% in males [2]. In the Sivas region, females had 50% seropositivity versus 30% in males [1]. This is likely due to the longer lifespan of breeding ewes in flocks, their retention for multiple lambing cycles, and the potential for vertical transmission to lambs, which maintains the infection cycle. However, some studies, such as the one in Croatia, found no significant sex difference [10], suggesting that management and culling practices can modulate this effect.

Flock management practices are critical modulators of risk. The purchase of replacement ewes is a major risk factor for introducing MVV into a naïve flock [19]. In Brazil, the acquisition of animals from other states was identified as a key risk factor [17]. Conversely, practices such as conducting a defined breeding season, supplying concentrated feed, and separating the breeding stock before birth were found to be protective in a Brazilian study [8]. The presence of cats on the farm was paradoxically associated with increased risk in the same study, possibly as a marker of lower biosecurity standards [8].

Viral Genetic Diversity and Its Epidemiological Implications

The global epidemiology of MVV is further complicated by the virus's high genetic heterogeneity, particularly in the env gene encoding the surface glycoprotein (SU). This genetic diversity has led to the classification of SRLVs into distinct genotypes (A, B, C, D, E, F), with genotype A (MVV-like) being the most prevalent worldwide. Within genotype A, multiple subtypes (A1-A22) have been described, often with geographic clustering. For instance, Chinese MVV strains from Inner Mongolia have been characterized as genotype A2, closely related to US strains [12, 20]. In Germany, while serotyping suggested the presence of genotype B (CAEV-like) for the first time in that country, molecular genotyping of the same samples identified only genotype A (A1, A3, A21, and A21-like), highlighting the discordance between serological and molecular typing methods [19]. This genetic diversity has profound implications for diagnostic test performance. Commercial ELISAs, which are typically based on antigens from a limited number of reference strains, may fail to detect antibodies against divergent field strains, leading to false-negative results and underestimation of true prevalence. This is a critical consideration for surveillance programs, as demonstrated by the development of a bead-based multiplex immunoassay in Norway specifically tailored to the circulating local strain [3]. The use of peptide-based ELISAs targeting conserved epitopes, such as those derived from the gag protein, offers a potential solution to improve cross-reactivity and diagnostic sensitivity across diverse viral strains [32].

The Role of Coinfections and Emerging Epidemiological Patterns

MVV does not exist in isolation, and its epidemiology is increasingly understood in the context of coinfections. Coinfection with Jaagsiekte sheep retrovirus (JSRV), the causative agent of ovine pulmonary adenocarcinoma, is particularly significant. In Romania, 47.6% of sheep with JSRV-induced tumors were also infected with MVV [44], while in China, 0.94% of slaughtered rams showed concurrent infection [39]. The pathological consequences of this coinfection are synergistic, with coinfected animals showing more severe interstitial pneumonia and lymphoid hyperplasia compared to those infected with JSRV alone [44]. This suggests that MVV infection may exacerbate the pathology of other respiratory pathogens, a hypothesis supported by transcriptomic studies showing that MVV infection upregulates a suite of pro-inflammatory chemokines (CXCL9, CXCL10, CXCL13) and recruits B cells, CD4+ and CD8+ T cells, and macrophages to the lung [31]. Coinfection with Mycobacterium avium subsp. paratuberculosis (MAP) is also common, with a study in Sardinia finding that 10.6% of ewes were positive for MAP, and that MVV positivity significantly affected milk coagulation properties [14]. Furthermore, MVV has been detected in the epididymis of rams coinfected with Brucella ovis, suggesting that concurrent infections may facilitate venereal shedding of MVV [30]. These findings point to a complex network of pathogen interactions that shape the clinical and epidemiological impact of MVV at the population level.

Transmission Dynamics and Risk Factors for MVV

The transmission dynamics of Maedi-Visna Virus (MVV) are governed by a complex interplay of viral, host, environmental, and management-related factors that collectively determine the patterns of infection within and between sheep populations. As a lentivirus, MVV establishes a lifelong, persistent infection characterized by prolonged latency, slow clinical progression, and intermittent viral shedding, which collectively shape its epidemiological profile. Understanding these dynamics is paramount for designing effective control and eradication programs, particularly given the absence of vaccines or curative therapies [1, 16, 18]. The virus is shed primarily through respiratory secretions, colostrum, and milk, with transmission occurring via both horizontal and vertical routes, though the relative contribution of each pathway varies significantly under different management systems [13, 18, 23].

Horizontal Transmission: The Dominant Route

Horizontal transmission, particularly through direct contact between infected and susceptible animals, is widely regarded as the primary mechanism sustaining MVV within flocks. The virus is present in high concentrations in respiratory secretions, and the most efficient route of spread is via aerosol or droplet transmission during close, prolonged contact [13, 18]. This is especially pronounced under intensive housing conditions where sheep are confined in close quarters, facilitating the exchange of infectious respiratory droplets. Illius et al. [13] developed a mathematical epidemiological model that starkly quantified this phenomenon, demonstrating that transmission rates among housed sheep are approximately 1,000 times faster than when sheep are at pasture. Their model indicated that even brief periods of housing, as short as a few days per year, in groups of approximately 50 sheep could result in a doubling of prevalence annually from a low initial incidence. Conversely, ewes kept entirely at grass experienced negligible transmission, and the model predicted that pre-existing infection would naturally die out as older, infected ewes were replaced, effectively “curing” the flock without intervention [13]. This finding underscores the profound impact of management intensity on transmission dynamics and explains the high prevalence rates observed in intensively managed dairy and meat production systems globally.

The biological basis for this efficiency lies in the virus’s tropism for cells of the monocyte/macrophage lineage, which are abundant in the respiratory tract. Infected macrophages in the lungs and airways shed virus into respiratory secretions, and the close proximity of animals in barns or sheds allows for efficient inhalation of aerosolized particles by naïve pen-mates [4, 16, 35]. The work of Shi et al. [31] provided transcriptomic evidence of the robust immune response mounted in the lungs of infected sheep, with upregulation of chemokines such as CXCL13, CXCL8, CXCL9, CXCL10, and CCL2, and infiltration of B cells, CD4+ and CD8+ T cells, and macrophages. This inflammatory milieu, while part of the host response, paradoxically creates a microenvironment rich in target cells, potentially enhancing local viral replication and shedding.

Vertical and Lactogenic Transmission

While horizontal transmission is the dominant force in most settings, vertical transmission, from ewe to lamb, plays a critical role in perpetuating infection across generations. The primary route of vertical transmission is lactogenic, through the ingestion of infected colostrum and milk [18, 23, 50]. The virus is shed in milk within infected macrophages, and lambs consuming contaminated colostrum are at risk of establishing infection early in life. Gayo et al. [23] demonstrated viral detection in milk samples from 16 of 39 infected sheep, confirming the potential for lactogenic transmission. Their immunocytochemical analysis revealed that viral positivity in milk was exclusively associated with macrophages, with no evidence of infection in epithelial cells, highlighting the role of these migratory cells as vehicles for viral dissemination.

However, the efficiency of maternal transmission is a subject of ongoing debate. Illius et al. [13] argued that maternal transmission plays only a small role in overall flock dynamics, noting that lambs from infected ewes have a low probability of being directly infected by them. They posited that because only a small proportion of lambs need to be retained to maintain flock size, the impact of vertical transmission on population-level prevalence is limited. This perspective is supported by the observation that in many flocks, seroprevalence increases markedly with age, suggesting that cumulative horizontal exposure over an animal’s lifetime is a more significant driver of infection than early-life acquisition [1, 10, 24]. Turan and Yurt [1] reported a progressive increase in seropositivity with advancing age in Kangal Akkaraman sheep, with older animals showing significantly higher rates than lambs and yearlings. Similarly, Kalogianni et al. [24] observed that point-seroprevalence in intensively reared dairy sheep increased with age, and the high incidence rates (33.6 new cases per 100 sheep-semesters) they recorded underscored the importance of ongoing horizontal transmission within adult cohorts.

Iatrogenic and Other Atypical Transmission Routes

Beyond the classical routes, emerging evidence points to iatrogenic transmission as a potentially underappreciated mechanism. The detection of MVV proviral DNA and antigen in post-vaccination granulomas by Miguel et al. [49] raises the possibility that contaminated needles or vaccination equipment could serve as fomites for viral spread. This is particularly concerning in intensive management systems where large numbers of animals are processed through handling facilities. Additionally, the demonstration of MVV in the epididymis of rams co-infected with Brucella ovis by Preziuso et al. [30] suggests that venereal shedding in semen may occur, especially in the context of concurrent infections that compromise the reproductive tract’s integrity. This finding has implications for the trade of breeding rams and the potential for introduction of MVV into naïve flocks through semen, though the epidemiological significance of this route under natural breeding conditions remains to be fully quantified.

Host Genetic Factors and Susceptibility

A major breakthrough in understanding MVV transmission dynamics has been the identification of host genetic determinants of susceptibility, most notably the transmembrane protein 154 gene (TMEM154). Multiple studies across diverse geographic regions and breeds have consistently demonstrated that polymorphisms in TMEM154, particularly at codon 35 (E35K), are strongly associated with resistance or susceptibility to MVV infection [6, 19, 22, 26]. Riggio et al. [6] found a significant association between TMEM154 genotypes and seroprevalence in Valle del Belìce sheep, with no seropositive individuals carrying the putatively resistant KK genotype. Yaman et al. [22] extended these findings to Turkish sheep, reporting that ewes with one or two copies of highly susceptible haplotypes (full-length E35 variants) had a three-fold greater risk of infection compared to those with combinations of K35 and deletion variants. Critically, Jones et al. [26] provided longitudinal evidence that a ram homozygous for the K allele maintained very low viral loads and apparently cleared infection to below detectable limits over a 16-month observation period, adding functional validation to the epidemiological associations.

The mechanism by which TMEM154 influences susceptibility is not fully elucidated, but the protein is thought to be involved in host-virus interactions at the cell surface, potentially affecting viral entry or early replication events. The presence of these resistance alleles in native breeds at varying frequencies has significant implications for transmission dynamics. In populations where resistant genotypes are prevalent, the effective reproductive number (R₀) of MVV may be substantially reduced, slowing the spread of infection even in the presence of intensive management practices. Conversely, breeds or flocks with a high frequency of susceptible haplotypes may experience explosive outbreaks under conducive management conditions. Frölich et al. [19] reported that seroprevalence was significantly lower in Pomeranian Coarsewool sheep carrying the K allele at codon 35 and/or the M allele at codon 44, while seropositivity was significantly higher in sheep with one or two I alleles at codon 70. These findings highlight the potential for selective breeding programs to reduce population-level susceptibility, a strategy that could complement traditional test-and-cull approaches.

Environmental and Management Risk Factors

A constellation of environmental and management factors has been consistently identified as modulating the risk of MVV transmission. The single most important factor is the degree of confinement and housing intensity. As discussed, the work of Illius et al. [13] established that housing is overwhelmingly the primary driver of transmission, with negligible spread occurring at pasture. This is corroborated by numerous seroprevalence studies that have documented higher infection rates in intensively managed dairy and meat flocks compared to extensive, pasture-based systems [2, 8, 24]. Idres et al. [2] reported that industrialized farming in high-prevalence regions of Algeria was a significant driver of seropositivity, while Vieira et al. [8] found that conducting a breeding season, supplying concentrated feed, and separating the breeding stock before birth were factors associated with protection in Brazilian flocks. Conversely, the same study identified breeding on pasture and keeping cats close to the flock as risk factors, though the biological rationale for the latter remains speculative [8].

The purchase of replacement stock is another critical risk factor for the introduction and spread of MVV. Frölich et al. [19] identified the purchase of ewes as the main environmental risk factor for seropositivity in German Pomeranian Coarsewool sheep, a finding echoed by Yizengaw et al. [15] who incriminated Awassi cross sheep distributor farms and ranches as sources of infection in Ethiopia. The introduction of a single seropositive animal into a naïve flock can serve as the index case for a multi-year outbreak, as the long incubation period and intermittent shedding allow the virus to spread undetected for months or years before clinical signs emerge [18]. This underscores the critical importance of quarantine and pre-entry testing protocols for all incoming animals.

Geographic location and regional prevalence patterns also exert a strong influence on risk. Studies from Croatia [10], Turkey [1, 22], Algeria [2], and Ethiopia [15] have all documented significant variation in seroprevalence across districts or provinces within the same country. Pavlak et al. [10] reported that seroprevalence in Istria County, Croatia, was 4.77 times higher than in other examined areas, with an odds ratio of 5.66. Similarly, Turan and Yurt [1] observed district-based seroprevalence rates ranging from 13.04% to 82.60% in the Sivas region of Turkey. These geographic disparities likely reflect differences in management intensity, breed composition, historical introduction events, and the presence of specific viral strains with varying transmissibility.

Age, Sex, and Breed as Risk Factors

The relationship between age and MVV seroprevalence is consistently positive across studies, reflecting the cumulative nature of exposure over an animal’s lifetime. Turan and Yurt [1] reported a progressive increase in seropositivity with advancing age in Kangal Akkaraman sheep, a pattern also observed by Kalogianni et al. [24] in intensively reared dairy ewes. However, the relationship is not always linear. Al-Baroodi et al. [41] paradoxically found the highest prevalence in sheep less than one year old (36.5%) compared to older animals (8.4%) in Nineveh, Iraq, suggesting that in some high-prevalence settings, early lactogenic transmission may predominate. Idres et al. [2] reported a peak in seroprevalence among 1–5-year-olds (10.43%) in Algeria, with lower rates in younger and older cohorts, potentially reflecting a combination of early exposure and subsequent mortality or seroreversion in aged animals.

Sex-based differences in seroprevalence have been reported, though they are not universally observed. Idres et al. [2] found significantly higher seroprevalence in females (20.44%) compared to males (3.68%) in Algeria, attributing this to females’ prolonged herd retention and the risks associated with vertical transmission. Turan and Yurt [1] similarly reported 50% seropositivity in females versus 30% in males. However, Pavlak et al. [10] found no statistically significant differences between sexes in Croatian flocks, and Yizengaw et al. [15] also reported no significant sex effect in Ethiopia. The apparent female bias in some studies may be confounded by management practices, as females are typically retained in the flock for multiple years of breeding, providing more opportunities for horizontal exposure, whereas males are often culled earlier or kept in smaller, isolated groups.

Breed effects on susceptibility are well-documented and likely reflect both genetic differences in TMEM154 allele frequencies and management practices associated with specific breeds. Pavlak et al. [10] reported that Istrian Pramenka and Jezersko-Solcava sheep had significantly higher seroprevalence (22.97% and 23.53%, respectively) compared to Krk, Pag, and Romanov breeds (<2%). The odds ratio for Istrian Pramenka compared to Pag sheep was 22.51, indicating a dramatic breed-associated risk. Bayraktar et al. [48] found that White Karaman–Kangal sheep were 18 times more likely to be infected than Red Karaman sheep. These breed differences are not solely attributable to genetic susceptibility; they also reflect regional management traditions, housing systems, and the historical presence of infection in specific populations. Nonetheless, the identification of breeds with inherently higher resistance, such as those carrying protective TMEM154 alleles, offers a pathway for genetic improvement of flock resistance.

Co-infections and Their Impact on Transmission

The presence of concurrent infections with other pathogens can modulate MVV transmission dynamics by altering host susceptibility, viral shedding, or diagnostic test performance. Co-infection with Jaagsiekte sheep retrovirus (JSRV), the causative agent of ovine pulmonary adenocarcinoma (OPA), has been documented in multiple settings. Duan et al. [39] confirmed concurrent JSRV and MVV infection in Dorper rams in Inner Mongolia, China, and Hodor et al. [44] reported a co-infection rate of 47.6% in OPA cases in Romania. The immunosuppressive effects of MVV infection may predispose animals to secondary infections, while the inflammatory lung pathology induced by both viruses could enhance respiratory shedding and transmission. Similarly, co-infection with Mycobacterium avium subspecies paratuberculosis (MAP) has been studied, with Pazzola et al. [14] reporting that MVV and MAP co-positivity affected milk composition and coagulation traits in Sarda ewes. The interaction between MVV and Brucella ovis in rams, as demonstrated by Preziuso et al. [30], may facilitate venereal shedding of MVV, introducing an additional transmission route that would not exist in the absence of the co-pathogen.

Diagnostic Implications for Transmission Studies

Accurate detection of infected animals is fundamental to understanding and interrupting transmission dynamics. However, the long and variable latency period between infection and seroconversion, coupled with the phenomenon of seroreversion, complicates epidemiological studies and control programs. Illius et al. [13] demonstrated the existence of an “epidemiological latency”, a time delay between infection and infectiousness that apparently exceeds the delay between infection and seroconversion. This means that animals may test seropositive before they become infectious, or conversely, may be infectious during the window period before antibodies are detectable. Kalogianni et al. [24] prospectively documented that 8.1% of infected animals seroreverted and 10.3% showed an intermittent presence of antibodies over a two-year period, confirming the risk of misdiagnosis in cross-sectional surveys. Jones et al. [26] further demonstrated that six of 12 naturally infected rams tested negative in one or more diagnostic assays at one or more time points, underscoring the fallibility of single-test, single-time-point screening programs. These diagnostic challenges have profound implications for transmission modeling, as they introduce uncertainty into estimates of prevalence, incidence, and the force of infection. The development of more sensitive and specific assays, such as the bead-based multiplex immunoassay tailored to local viral strains described by Borge et al. [3], or the peptide-ELISA developed by Koçkaya et al. [32], may improve detection and provide more accurate data for transmission studies.

Clinical Manifestations and Pathological Lesions in Sheep

Maedi-Visna virus (MVV) infection in sheep constitutes a complex, progressive, multisystemic syndrome characterized by an extraordinarily protracted clinical latency, often extending for months to years, before the insidious onset of overt disease. The etiological agent, a lentivirus within the family Retroviridae, establishes a lifelong infection that evades immune clearance through strategic integration into the host genome and replication within cells of the monocyte/macrophage lineage [16, 25]. The clinical manifestations and associated pathological lesions are the direct consequence of a chronic, low-grade inflammatory response driven by persistent viral replication, ultimately leading to tissue destruction and fibrosis in multiple organ systems. The World Organisation for Animal Health (WOAH) recognizes MVV as a significant global pathogen due to its economic impact and the challenges it poses to sheep health and welfare.

Respiratory Form (Maedi)

The respiratory manifestation, known as maedi (Icelandic for dyspnea), is arguably the most frequently recognized clinical form and represents the primary cause of morbidity in infected flocks. The clinical trajectory begins with a subtle, progressive exercise intolerance, often initially observed in ewes during the postpartum period when metabolic demands are highest [16, 18, 50]. Affected animals exhibit a gradual increase in respiratory rate and effort, which may be exacerbated by stress or concurrent infections. As the disease advances, the hallmark sign, a forced, often audible, abdominal expiratory effort, becomes prominent, yet coughing is notably absent unless secondary bacterial infections supervene. The course of clinical disease, once apparent, is relentlessly progressive, spanning weeks to months, culminating in severe respiratory distress, cachexia, and ultimately death.

The pathological substrate underlying this clinical syndrome is a severe, diffuse, lymphoproliferative interstitial pneumonia. On gross inspection, the lungs of affected sheep are characteristically enlarged, non-collapsed, and heavy, failing to deflate upon opening the thoracic cavity [39, 47]. The parenchyma exhibits a firm, rubbery, or "spongy" consistency, and the cut surface may reveal a greyish-tan discoloration with a loss of normal alveolar architecture. Importantly, the lungs are "dry," lacking the frothy exudate typical of bacterial pneumonia, though a white foamy fluid may occasionally be observed in the trachea in cases of concurrent Jaagsiekte sheep retrovirus (JSRV) infection [39]. Hilar and mediastinal lymph nodes are often markedly enlarged, reflecting the robust lymphoid hyperplasia central to the disease process [39].

Histopathologically, the lesion is defined by a diffuse thickening of the interalveolar septa due to the infiltration of mononuclear cells, predominantly lymphocytes (both CD4+ and CD8+ T cells), macrophages, and plasma cells, coupled with a proliferation of type II pneumocytes and smooth muscle hyperplasia [31, 35]. This creates a characteristic histologic picture often described as "lymphoproliferative" or "lymphocytic interstitial pneumonia." Immunohistochemical studies have demonstrated that B cells, CD4+ and CD8+ T cells, and macrophages are the most prevalent immune cells infiltrating the lung parenchyma [31]. A hallmark feature is the presence of prominent lymphoid follicles with germinal centers arranged in a peribronchiolar and perivascular distribution, a phenomenon known as lymphoid hyperplasia [31, 44, 47]. In advanced stages, fibromuscular hyperplasia further contributes to the obliteration of alveolar spaces, leading to irreversible respiratory compromise. Transcriptomic analyses of infected lungs reveal a massive dysregulation of gene expression, with upregulation of multiple chemokines and cytokines, including CXCL13, CXCL6, CXCL8, CXCL9, CXCL10, CCL2, interferon-gamma (IFN-γ), and matrix metalloproteinase 9 (MMP9), which orchestrate the relentless recruitment and activation of inflammatory cells [31]. The severity of the pulmonary lesions can be exacerbated by coinfection with other respiratory pathogens, such as JSRV, where concurrent infection leads to a more complex pathological picture involving neoplastic transformation alongside the inflammatory interstitial changes [39, 44].

Neurological Form (Visna)

The neurological form, known as visna (Icelandic for wasting), is characterized by a progressively debilitating paralysis and neurological deficits. While less common than the respiratory form in some regions, it can be a major clinical feature in others [16, 47]. The classic presentation involves a gradual onset of hindlimb paresis and ataxia, which typically begins asymmetrically. Animals may exhibit a "dog-sitting" posture, knuckling of the fetlocks, and a progressive loss of coordination that advances to complete paralysis of the hindquarters [16, 47]. Forelimb involvement is less common and usually occurs later in the disease course. Proprioceptive deficits are a key clinical finding, and affected sheep may also show subtle cranial nerve signs, including head tremors, nystagmus, and facial paralysis. The neurological signs are often accompanied by a progressive loss of body condition despite adequate appetite, a reflection of the systemic wasting nature of the disease.

The pathological lesions are confined to the central nervous system (CNS) and are primarily localized to the white matter of the brainstem, cerebellum, and spinal cord. The defining lesion is a chronic, non-suppurative demyelinating leukoencephalomyelitis. Histopathologically, this is characterized by perivascular cuffing by mononuclear cells, lymphocytes, plasma cells, and macrophages, accompanied by a diffuse infiltration of the neuroparenchyma by activated microglial cells and macrophages. These foci of inflammation are associated with areas of primary demyelination, which is thought to result from a combination of direct viral cytopathic effects on oligodendrocytes and bystander damage from the inflammatory response [16]. In advanced cases, areas of malacia (tissue softening) may be observed, with the accumulation of lipid-laden "gitter cells" (macrophages) in the affected neuropil [47]. It is crucial to note, however, that the detection of proviral DNA and viral antigen in the CNS by methods such as PCR and immunohistochemistry is inconsistent. Several studies have reported difficulty in detecting MVV p28 antigen in brain tissue even from animals with confirmed neurological lesions, suggesting a low viral burden or a heavily restricted replication state within the CNS during the late stages of disease [4, 29]. This highlights the immunopathogenic nature of the CNS lesion, where the host immune response, rather than unchecked viral replication, is the primary driver of tissue damage.

Mammary Form (Indurative Mastitis)

MVV infection of the mammary gland is a common and economically significant manifestation, often presenting as a chronic, indurative mastitis that markedly reduces milk production and alters milk composition [7, 14, 23]. The clinical signs are subtle: affected ewes may have "hard" or "firm" udders that fail to "bag up" adequately after lambing, and lambs may show poor growth rates due to reduced milk intake [7, 23]. The condition is frequently mistaken for chronic bacterial mastitis, but the milk is typically not grossly abnormal, and bacteriological cultures are negative [7].

Grossly, the affected mammary gland is firm, fibrous, and may be reduced in size, reflecting extensive atrophy of the secretory parenchyma. On cut section, there is a loss of the normal lobular architecture, replaced by dense, white fibrous tissue. The pathological hallmark is a lymphohistiocytic interstitial mastitis, which can vary from minimal, focal infiltrates to a severe, diffuse effacement of the gland [7, 23]. Minimal lesions are characterized by small, discrete foci of lymphocytes and macrophages surrounding the alveoli and interlobular septa. In moderate to severe cases, the infiltrates become coalescing, leading to atrophy of alveolar epithelial cells, deposition of dense collagenous connective tissue (fibrosis), and, in extreme cases, dystrophic calcification of the affected tissue [7]. Immunohistochemistry has localized viral antigen (p28) to macrophages, dendritic cells, and even epithelial and endothelial cells within the gland, confirming direct viral involvement in the pathogenesis [7, 23]. The detection of MVV provirus in milk samples and shed macrophages further underscores the role of the mammary gland as a site of viral replication and excretion, contributing to transmission via colostrum and milk [23]. The effect on milk yield and quality is profound: seropositive ewes have been shown to produce milk with a higher somatic cell count and altered curd-firming properties, negatively impacting cheese-making potential [14].

Arthritic and Other Systemic Manifestations

Chronic arthritis, while less prominent than in caprine arthritis-encephalitis virus (CAEV) infection in goats, is a recognized component of MVV disease in sheep [4, 16, 35]. It typically presents as a chronic, progressive lameness affecting one or more joints, most commonly the carpal (knee) joints. Affected joints are swollen, warm, and painful upon manipulation, leading to stiffness and a reluctance to move. In severe cases, the animal may become recumbent. Pathologically, the lesion is a chronic proliferative synovitis. The synovial membrane becomes thickened, hyperemic, and infiltrated by lymphocytes, plasma cells, and macrophages. This inflammatory process leads to villous hypertrophy of the synovium, erosion of articular cartilage, and ultimately, fibrosis and ankylosis of the joint. The detection of MVV nucleic acid in joint tissues has been documented, albeit at a lower frequency than in the lungs, confirming the tropism of the virus for synovial cells [4, 35].

Beyond these four major forms, MVV infection is a systemic disease. The virus establishes a persistent reservoir in lymphoid tissues, including the spleen, bone marrow, and lymph nodes draining and non-draining target organs, as demonstrated by the presence of proviral DNA in these sites years after experimental infection [25, 29]. This widespread lymphoid distribution means that infection can affect nearly any organ system. For instance, the development of post-vaccination granulomas has been described in naturally infected sheep, suggesting that localized immune activation can trigger aberrant inflammation at sites distant from the primary target organs [49]. Additionally, the virus can infect the epididymis, particularly in the context of concurrent infection with Brucella ovis, potentially leading to viral shedding in semen and complicating control efforts [30]. The systemic, low-grade inflammation driven by persistent MVV infection also contributes to the progressive emaciation seen in many animals, likely mediated by a chronic catabolic state induced by elevated levels of pro-inflammatory cytokines. The genetic susceptibility of the host, particularly polymorphisms in the TMEM154 gene, modulates the risk and severity of infection, with certain alleles conferring relative resistance or susceptibility to the development of these clinical and pathological outcomes [6, 19, 22, 26].

Diagnostic Approaches for MVV Detection and Surveillance

The accurate and timely diagnosis of Maedi-Visna virus (MVV) infection represents one of the most formidable challenges in small ruminant medicine. The virus’s lifelong persistence, protracted clinical latency, high genetic heterogeneity, and complex immunopathogenesis demand a multi-faceted diagnostic paradigm that moves far beyond simple serological screening. A comprehensive diagnostic strategy must integrate serological, molecular, pathological, and, increasingly, genomic approaches to achieve the sensitivity and specificity required for effective surveillance and control programs. The World Organisation for Animal Health (WOAH) recognizes MVV as a pathogen of significant economic consequence, yet no single “gold standard” test exists; rather, the diagnostic arsenal must be deployed strategically based on the epidemiological context, the purpose of testing (e.g., individual certification versus herd-level eradication), and the circulating viral strains.

Serological Diagnostics: The Cornerstone and Its Limitations

Serological detection of anti-MVV antibodies remains the most widely employed diagnostic approach globally, owing to its relative simplicity, cost-effectiveness, and suitability for large-scale screening. The humoral immune response to MVV is robust and persistent, directed primarily against the major core protein p25/p28 (Gag) and the envelope glycoproteins (gp135/SU and gp46/TM) [16]. However, the diagnostic landscape is complicated by the considerable genetic and antigenic diversity of small ruminant lentiviruses (SRLVs), which can lead to variable test performance across different geographic regions and breeds.

Enzyme-Linked Immunosorbent Assay (ELISA). Commercial indirect ELISA kits, such as the ID Screen® MVV/CAEV Indirect (IDvet), IDEXX MVV/CAEV p28 Ab Verification Test, and Elitest MVV/CAEV (Hyphen Biomed), form the backbone of most national surveillance programs. A landmark Bayesian latent class analysis by Jerre et al. (2022) rigorously evaluated these three commercial platforms using 615 samples from six Norwegian flocks. The study revealed stark differences in performance: ID Screen and Elitest demonstrated significantly higher sensitivity estimates (99.3% and 97.4%, respectively) compared to IDEXXp28 (79.5%), while IDEXXp28 and ID Screen exhibited superior specificity (99.7% and 99.1%) relative to Elitest (93.7%) [9]. This study is critical, as it underscores that no single commercial test is optimal for all purposes. For situations demanding high positive predictive value, such as confirming infection in low-prevalence populations or for certification of individual animals, a serial testing strategy combining ID Screen (screening) followed by Elitest (verification) yielded the highest combined sensitivity (96.7%) and specificity (100.0%) [9]. Conversely, for initial herd screening where missing a positive animal is more consequential, a highly sensitive test like ID Screen alone is preferable.

The performance of these tests is not static. A validation study of a CAEV/MVV indirect ELISA in U.S. sheep, using radioimmunoprecipitation as the reference standard, reported a sensitivity of only 86.0% and a specificity of 95.9% [28]. The authors directly attributed the reduced sensitivity to phylogenetic differences in the MVV gag sequence between the test antigen source and circulating U.S. strains [28]. This finding is a stark warning: commercially available ELISAs, often based on prototype strains (e.g., MVV K1514 or CAEV Cork), may fail to detect infection in populations harboring divergent viral lineages. The prevalence of such diagnostic escape variants is likely underestimated and poses a significant threat to eradication efforts.

Agar Gel Immunodiffusion (AGID). The AGID test, historically the first standardized serological method, detects precipitating antibodies against viral antigens, typically p28 and gp135. While highly specific (approaching 100%), its sensitivity is markedly lower than modern ELISAs. Studies utilizing AGID continue to appear in the literature, particularly in resource-limited settings. For instance, a survey of sheep in Porto Acre, Brazil, using the p28-based AGID, reported a seropositivity of 8.2% [17], while a larger study in the Paraná state of Brazil found only 1.4% positivity using a micro-AGID variant [8]. In Şanlıurfa, Turkey, AGID testing of 1096 sera revealed a seroprevalence of 10.5% [45], and in another Brazilian study, the IDGA technique yielded a 2.02% prevalence [27]. The consistently lower detection rates compared to ELISA, even within the same geographic regions, confirm that AGID is inadequate for modern surveillance and should be relegated to historical comparisons or as a confirmatory test in the absence of more sensitive tools. The WOAH Terrestrial Manual currently recommends ELISA as the preferred serological test for international trade.

Novel and Enhanced Serological Platforms. To overcome the limitations of genetic variability, innovative serological approaches are being developed. One promising avenue is the use of synthetic peptides representing conserved B-cell epitopes. Koçkaya et al. (2024) developed a peptide-ELISA using predicted epitopes from the Gag protein. Two peptides, CKQGSKE and CRPQGKAGHKG, demonstrated high diagnostic performance, with sensitivity and specificity values of 91.6% and 92.8%, respectively, compared to a commercial kit [32]. This approach offers the potential for standardized, reproducible antigen production that can be tailored to regional viral strains.

Another sophisticated advancement is the bead-based multiplex fluorescent immunoassay. Borge et al. (2024) developed an assay for the Norwegian sheep population that included recombinant Norwegian p25, p16–25, and SU5 antigens alongside commercial TM-A. This multiplex format allows for the simultaneous detection of antibodies against multiple viral epitopes, increasing the breadth of detection and providing a serological “fingerprint” of the infecting strain. The assay achieved analytical sensitivity equal to or greater than commercial ELISA, with specificities for individual antigens ranging from 91.7% to 95.0% [3]. This technology is particularly valuable for populations where the circulating strain is known to differ from standard antigens, as was the case in the 2019 Norwegian outbreak [3, 9].

Interpretational Pitfalls: Intermittent Seroreversion. A critical and often overlooked challenge in serological surveillance is the phenomenon of intermittent antibody detection or seroreversion. A prospective two-year study of intensively reared dairy sheep revealed that, remarkably, 8.1% of infected animals seroreverted and 10.3% showed an intermittent presence of antibodies during the observation period [24]. This is not a failure of the test, but a reflection of the complex host-virus interaction. During clinical latency, viral replication may be so restricted that antibody titers wane below detectable thresholds. This finding has profound implications: cross-sectional serological surveys may significantly underestimate true prevalence, and test-and-cull programs based on a single negative test result are highly unreliable. Flocks can harbor a “silent” reservoir of infected animals that periodically test negative, perpetuating transmission.

Molecular Diagnostics: Direct Detection of Viral Nucleic Acid

Polymerase chain reaction (PCR)-based methods offer the critical advantage of detecting proviral DNA integrated into the host genome, irrespective of the host's antibody status. This is essential for identifying recently infected animals (the "diagnostic window" before seroconversion), animals with low or waning antibody titers, and those infected by divergent strains not recognized by serological assays.

Target Genes and Assay Design. The choice of PCR target region is paramount. The gag (p28) and pol genes are relatively conserved, while env and the Long Terminal Repeat (LTR) are hypervariable. A direct comparison of nested PCR assays targeting the gag versus the LTR region in bronchoalveolar lavage samples from Brazilian sheep demonstrated the profound impact of primer choice. The LTR-targeted assay detected 37.9% of samples as positive, while the gag-targeted assay detected only 10.3% [37]. The LTR’s higher copy number per integrated provirus and its role as a regulatory region may enhance detection, but its variability also risks false negatives if primers are not matched to the circulating strain. This study starkly illustrates that a negative PCR result is only relevant to the specific primers used; a negative gag PCR does not rule out infection.

Tissue Tropism and Sampling Strategy. The distribution of MVV provirus within the host is not uniform, and this dictates optimal sampling. Proviral DNA can be detected in a wide range of tissues years after infection. Preziuso et al. (2018) detected proviral DNA by PCR in all sampled lymphoid tissues (spleen, bone marrow, mesenteric, popliteal, and mammary lymph nodes) of sheep three years after experimental respiratory infection, confirming lymphoid tissues as major viral reservoirs even in the absence of active disease [25]. This widespread distribution explains the difficulty of clearing infection.

For molecular diagnosis in live animals, blood (specifically the buffy coat containing monocytes/macrophages) is the most accessible sample. A large Indian study screening 701 biological samples found the highest positivity rate in blood (14.59%), followed by joint tissue (13.72%), lung (8.6%), and mammary gland (8.1%) [35]. However, a separate study from India reported that lung tissue yielded the highest positivity (25.7%) among post-mortem samples, followed by mammary gland (14.8%) [4]. This discrepancy highlights that while blood is useful for ante-mortem screening, viral load in peripheral blood can be extremely low during clinical latency. PCR testing of lung tissue or bronchoalveolar lavage fluid provides superior sensitivity for ante-mortem confirmation, and post-mortem lung and mammary gland are the gold standard tissues.

Quantitative PCR (qPCR). Quantification of proviral load offers insights into transmission risk and disease progression. A longitudinal study of naturally infected rams revealed dramatic fluctuations in both DNA and RNA viral loads over a 16-month period. Critically, six of 12 animals tested negative in at least one test (serology, DNA PCR, or RNA PCR) at some time points [26]. This reinforces the need for repeated testing over time. The same study found that a ram homozygous for the TMEM154 K35 resistance allele maintained extremely low, and eventually undetectable, viral loads, suggesting that host genetics profoundly influence the sensitivity of molecular detection [26].

Pathological and Immunohistochemical Confirmation

While serology and PCR are the mainstays of surveillance, histopathology and immunohistochemistry (IHC) provide definitive confirmation of MVV-associated disease and are essential for understanding pathogenesis. The hallmark lesion, progressive interstitial lymphoplasmacytic pneumonia, is characterized by infiltration of B cells, CD4+ and CD8+ T cells, and macrophages, along with lymphoid hyperplasia [31, 35]. IHC targeting the viral p28 capsid antigen is a powerful tool for visualizing viral distribution within these lesions.

Detection of p28 antigen in tissue sections is highly specific. In a study of 21 sheep with indurative mastitis, IHC localized MVV antigen to macrophages, dendritic cells, epithelial cells, and endothelial cells of the mammary gland, as well as in macrophages and dendritic cells of the supramammary lymph node [7]. This confirms the mammary gland as a primary site of replication and a major route of transmission to lambs. Interestingly, IHC and PCR have demonstrated viral presence in tissues even when serology is negative. Preziuso et al. (2004) reported one experimentally infected ewe that was seronegative for over a year yet had detectable p28 antigen and proviral DNA in the lungs [29]. Similarly, Gayo et al. (2019) found that six sheep with histopathological lesions of VM mastitis were seronegative, while IHC and PCR confirmed infection [23]. These cases represent diagnostic failures for serology-based programs and underscore the indispensable role of direct viral detection methods.

Further refinement involves the detection of specific immune cell infiltrates. RNA sequencing of MVV-infected lung tissues revealed a significant upregulation of chemokines like CXCL13, CXCL8, and CCL2, which recruit B cells, neutrophils, and macrophages, respectively [31]. IHC can be used to phenotype these infiltrates, demonstrating that the MVV-infected lung is dominated by B-cell follicles and a cytotoxic CD8+ T-cell response, a pattern that distinguishes MVV pneumonia from other chronic respiratory diseases [31, 35].

Advanced and Emerging Diagnostic Technologies

The frontiers of MVV diagnostics are being pushed by molecular evolution and immunoproteomics.

Next-Generation Sequencing (NGS) and Phylogenetic Analysis. The genetic characterization of circulating strains is fundamental to understanding test performance and viral spread. Whole-genome sequencing of Chinese MVV isolates revealed that they belong to genotype A2 and share only 77.1–86.8% nucleotide homology in gag and 67.7–75.5% in env with reference strains [12]. This extreme divergence is a direct cause of reduced diagnostic sensitivity when using assays designed against foreign strains. NGS is not a routine diagnostic tool but is essential for informing the design of region-specific PCR primers and recombinant antigens for serological assays, as was demonstrated in the Norwegian outbreak [3].

Genetic Susceptibility Testing (TMEM154 Genotyping). The discovery of the transmembrane protein 154 (TMEM154) gene as a major determinant of host susceptibility to MVV has opened the door to a novel form of “diagnostics”, genetic risk profiling. The E35K polymorphism (lysine at codon 35, the K allele) is strongly associated with resistance, while the glutamic acid (E) allele is associated with susceptibility. In a study of Valle del Belìce sheep, no individuals with the resistant KK genotype were seropositive, and a highly significant association (p < 0.001) was found between TMEM154 genotype and infection status [6]. Similarly, in Pomeranian Coarsewool sheep, seroprevalence was significantly lower in animals carrying the K allele at codon 35 and/or the M allele at codon 44 [19]. Most compellingly, a longitudinal study of naturally infected rams showed that the only animal homozygous for the K allele cleared infection to below detectable limits over time [26]. TMEM154 genotyping is not a diagnostic for infection, but it is a powerful predictive tool that can be integrated into eradication programs to identify genetically resistant replacement stock, as has been advocated for Turkish sheep [22].

In situ PCR and Antigen Detection in Semen. A particularly concerning facet of MVV epidemiology is potential venereal transmission. Preziuso et al. (2009) used a combination of IHC, liquid-phase PCR, and in situ PCR to demonstrate MVV p28 antigen and proviral DNA in the epididymal epithelium and interstitial macrophages of rams co-infected with Brucella ovis [30]. The in situ PCR technique confirmed the presence of provirus within epithelial cells, suggesting that the virus can be shed directly into the semen. This finding has significant implications for the use of artificial insemination and the movement of breeding rams, and it highlights the need for PCR testing of semen in high-value genetic stock.

Synthesis and Strategic Recommendations for Surveillance

No single diagnostic test is sufficient for MVV surveillance. The choice of test must be dictated by the objective. For national-level herd screening, a high-sensitivity commercial ELISA (e.g., ID Screen or Elitest) is appropriate, but any positive result should be interpreted with caution given potential false positives [9]. For eradication programs, a serial testing strategy using two tests with orthogonal performance characteristics (e.g., ID Screen for screening, Elitest for confirmation) is recommended to maximize the positive predictive value [9]. For confirming infection in seronegative animals with clinical signs, PCR on blood or bronchoalveolar lavage, ideally targeting the LTR region or a conserved gag sequence, should be performed. For post-mortem confirmation, histopathology with IHC for p28 is definitive.

The challenge of intermittent seroreversion [24] and the existence of seronegative carriers [23, 29] demands that surveillance programs employ repeat testing at intervals. The ultimate tool for population-level control may be genetic selection for TMEM154 resistance alleles [6, 19, 22]. By integrating serological screening, targeted molecular diagnostics, and host genotyping, a truly robust, next-generation surveillance framework can be established to combat this persistent and insidious pathogen.

Current Control Strategies and Future Directions for MVV Management

The management of Maedi-Visna Virus (MVV) infection presents one of the most formidable challenges in contemporary small ruminant medicine. Unlike many viral pathogens for which prophylactic vaccination or therapeutic intervention offers a viable path to control, MVV remains refractory to both approaches, necessitating a paradigm that relies exclusively on comprehensive biosecurity, rigorous diagnostic surveillance, and the emerging promise of host genetics [1, 16, 18, 50]. As a lentivirus that establishes lifelong infection characterized by prolonged immunological and clinical latency, MVV demands a control philosophy that is fundamentally different from that applied to acute viral infections. The current landscape is defined by a patchwork of national eradication programs, voluntary certification schemes, and farm-level interventions, all of which are constrained by the virus’s unique biology, the limitations of existing diagnostic tools, and the socio-economic realities of sheep production systems worldwide. The World Organisation for Animal Health (WOAH) recognizes MVV as a significant pathogen of small ruminants, yet international standards for control remain underdeveloped compared to those for diseases such as brucellosis or classical scrapie, reflecting both the complexity of the pathogen and the variability in national surveillance capacities.

The Current Control Paradigm: Test-and-Cull and Biosecurity

The cornerstone of MVV control in virtually all settings where eradication is attempted is the test-and-cull strategy, coupled with strict biosecurity measures designed to prevent introduction and interrupt transmission. This approach is predicated on the identification and removal of seropositive animals, thereby reducing the within-flock prevalence and, ideally, eliminating the virus entirely [13, 18, 19]. The feasibility of this approach, however, is deeply contingent on the epidemiological context. In high-prevalence, intensively managed dairy flocks, the economic and logistical burden of testing and removing large numbers of seropositive ewes can be prohibitive, often exceeding the perceived cost of the disease itself. Conversely, in low-prevalence orMVV-free flocks, a focused test-and-remove program targeting introduced animals or those identified through routine surveillance is far more sustainable. The mathematical modeling work of Illius et al. [13] provides a critical quantitative framework for this approach, demonstrating that MVV transmission is overwhelmingly a disease of housing, where sheep are maintained in close proximity. Their model estimates that transmission rates amongst housed sheep are approximately 1,000 times faster than when sheep are at grass, where transmission is negligible. This finding has profound implications for control: management practices that minimize the duration and intensity of housing, particularly during lambing and winter feeding, can dramatically reduce the force of infection. The model further reveals that maternal transmission plays a surprisingly minor role, with lambs from infected ewes having a low probability of direct infection. Consequently, a flock kept entirely at pasture is unlikely to experience sufficient transmission frequency for MVV to persist, and pre-existing infection should die out as older ewes are replaced, effectively “curing” the flock without the need for intensive testing. This insight challenges the traditional emphasis on colostrum management as the primary control point and redirects attention toward horizontal transmission in housed environments.

Despite the theoretical elegance of this model, several practical realities complicate its implementation. First, the prolonged and variable latency period between infection and seroconversion means that serological testing alone is insufficient to identify all infected animals, particularly in the early stages of an outbreak [13, 24]. Second, the phenomenon of seroreversion, whereby previously seropositive animals become seronegative, has been documented in longitudinal studies, complicating the interpretation of single-point testing and undermining the reliability of test-and-cull programs that rely on a single sampling occasion [24]. Kalogianni et al. [24] observed that 8.1% of infected animals seroreverted and 10.3% exhibited an intermittent presence of antibodies over a two-year prospective study in intensively reared dairy sheep. These serological patterns indicate a dynamic host-virus interaction that is poorly captured by static diagnostic approaches, and they underscore the risk of misdiagnosis in cross-sectional studies and in currently implemented testing and elimination programs. The presence of seronegative but proviral-positive animals, as demonstrated by PCR and immunohistochemistry in multiple studies [23, 29], further erodes the sensitivity of antibody-based control strategies.

Diagnostic Limitations and Advances in Surveillance

The accuracy of MVV diagnosis is the linchpin upon which all control efforts rest, and it is here that the field faces its most significant technical hurdles. The high genetic heterogeneity of MVV, driven by the error-prone reverse transcriptase of this lentivirus, has profound implications for diagnostic test performance across different geographic regions and even within individual flocks [3, 12, 37]. Commercial enzyme-linked immunosorbent assays (ELISAs) have largely replaced the older agar gel immunodiffusion (AGID) test as the primary screening tool, yet their sensitivity and specificity vary considerably depending on the viral strains circulating in the target population. A rigorous evaluation of three commercial ELISAs using Bayesian latent class analysis, a method that circumvents the need for a perfect reference standard, revealed significant differences in test performance [9]. The ID Screen® MVV/CAEV Indirect test exhibited the highest sensitivity (99.3%), while the IDEXX MVV/CAEV p28 Ab Verification Test showed significantly lower sensitivity (79.5%). However, the ID Screen and IDEXXp28 tests both demonstrated high specificity (99.1% and 99.7%, respectively), whereas the Elitest MVV/CAEV showed lower specificity (93.7%). The study recommended a serial testing strategy combining ID Screen for screening followed by Elitest for verification, which yielded the highest median positive predictive value, particularly in low-prevalence populations. This finding is of critical importance for eradication programs where false positives can lead to the unnecessary culling of valuable genetic stock.

The genetic variability of MVV poses a particular challenge for molecular diagnostics. The choice of primer sets for PCR, particularly whether they target the conserved gag gene or the more variable env and LTR regions, can dramatically affect detection rates. Marinho et al. [37] demonstrated that nested PCR targeting the LTR region yielded 37.93% positivity in bronchoalveolar lavage samples from Brazilian sheep, compared to only 10.34% for primers targeting the gag region, illustrating the superior sensitivity of LTR-based assays in populations where the circulating strains may diverge from reference sequences. This variability has led to the development of region-specific diagnostic tools. In Norway, where a national eradication program is underway, Borge et al. [3] developed a bead-based multiplex immunoassay that incorporates recombinant antigens based on the circulating viral strain identified from a recent outbreak. This tailored approach addressed the concern that commercial ELISAs, developed using reference strains from other continents, might fail to detect antibodies in the genetically distinct Norwegian MVV population. The analytical sensitivity of this multiplex assay was equal to or higher than that of commercial ELISAs, and the repeatability was acceptable, with coefficients of variation below 15% for most positive samples. Such in-country assay development represents a significant investment but may be necessary for effective surveillance in regions with unique viral lineages.

The development of peptide-based ELISAs offers another avenue for improving diagnostic accuracy while reducing reliance on whole-virus or recombinant protein antigens that may vary with viral evolution. Koçkaya et al. [32] identified B-cell epitopes of the MVV Gag protein through in silico prediction and demonstrated that peptides CKQGSKE and CRPQGKAGHKG achieved sensitivity and specificity values of 91.6% and 92.8%, respectively, when compared to a commercial ELISA. This approach not only offers the potential for standardized, synthetic antigens that can be produced consistently and at scale but also allows for the inclusion of epitopes from multiple viral subtypes to broaden diagnostic coverage. The identification of specific immunodominant epitopes also lays the groundwork for DIVA (Differentiating Infected from Vaccinated Animals) strategies, should a vaccine ever become available.

The Promise and Pitfalls of Genetic Resistance

Perhaps the most exciting development in MVV control in recent years is the identification of host genetic factors associated with resistance to infection. The transmembrane protein 154 gene (TMEM154) has emerged as a major candidate gene, with several studies demonstrating a consistent association between specific alleles and reduced susceptibility to MVV infection [6, 19, 22, 26]. The E35K single nucleotide polymorphism, which results in a glutamic acid (E) to lysine (K) substitution at codon 35, has been the most extensively studied. In North American sheep, homozygosity for the K35 allele has been associated with resistance to infection, and subsequent studies in Turkish, German, and Italian sheep populations have confirmed and extended these findings. Yaman et al. [22] conducted a large-scale serological census of 2,266 ewes from 11 Turkish flocks and found that ewes carrying one or two copies of highly susceptible TMEM154 haplotypes (full-length E35 variants) had a threefold greater risk of infection compared to those with K35 and deletion variants. Crucially, the K35 allele and deletion variants were present at low frequencies in native Turkish breeds, suggesting that selective breeding could increase their prevalence and reduce seroprevalence in affected flocks.

The mechanistic basis for this resistance is not fully understood, but the TMEM154 protein is expressed on the surface of lymphocytes and is thought to function as a receptor or co-receptor for MVV entry. The E35K substitution alters a highly conserved extracellular domain, potentially disrupting the interaction between the virus and the host cell. Riggio et al. [6] investigated TMEM154 genotypes in the Valle del Belìce sheep breed in Sicily and found that no individuals carrying the resistant KK genotype were seropositive, while seroprevalence among heterozygous EK animals was lower than among EE homozygotes. This complete association between the KK genotype and seronegativity is compelling evidence that this allele confers a high degree of protection, at least against the viral strains circulating in that population.

However, the story is not straightforward. Frölich et al. [19] examined TMEM154 variation in Pomeranian Coarsewool Sheep in Germany and found that the association between the KK genotype and seropositivity showed only a tendency toward significance (p = 0.088). The protective effect was more pronounced when sheep carrying the K allele at codon 35 and/or the M allele at codon 44 were analyzed together, suggesting that resistance may be polygenic or that the relevant protective haplotype extends beyond a single SNP. Furthermore, an isoleucine allele at codon 70 was associated with significantly higher seropositivity (p = 0.045), indicating that some TMEM154 variants may actually increase susceptibility. The presence of multiple viral genotypes in the German study, including genotype A (subtypes A1, A3, A21, and A21-like) and, for the first time in Germany, genotype B, raises the possibility that the protective effect of specific host alleles is strain-specific. A virus that enters a flock by evading the resistance conferred by TMEM154 K35 may rapidly spread, undermining the long-term efficacy of selection for a single allele.

The most dramatic demonstration of the potential of TMEM154-mediated resistance comes from a longitudinal study of naturally infected rams by Jones et al. [26]. Over 16 months, one ram homozygous for the K allele maintained very low viral loads in all assays (serology, DNA PCR, and RNA PCR) and, critically, cleared infection to below detectable limits at the final sampling time point. This is the first direct evidence that a naturally infected animal can clear MVV infection, a finding that contradicts the long-held dogma that lentiviral infection is invariably lifelong. If confirmed in larger studies, this observation would transform the control paradigm: rather than relying solely on test-and-cull, it may be possible to breed flocks in which infected animals spontaneously clear the virus, dramatically reducing transmission and potentially leading to herd immunity. The implications for eradication programs are profound, as the economic and welfare costs of culling would be substantially reduced.

Nevertheless, the practical implementation of TMEM154-based selection faces significant challenges. The low frequency of the protective K35 allele in many breeds, 0.151 in the Valle del Belìce, 0.128 in Pomeranian Coarsewool Sheep, and very low in many Turkish native breeds [6, 19, 22], means that selection would be slow and would require the introgression of the allele from other breeds, potentially compromising locally adapted traits. Moreover, the association between TMEM154 genotype and resistance appears to be population-specific and virus strain-dependent, meaning that a “one-size-fits-all” genetic solution is unlikely to be effective. The identification of additional host genes associated with resistance, such as those involved in the innate immune response, will be necessary to develop robust breeding strategies.

Management Interventions and the Role of Husbandry

Beyond testing and genetics, a suite of management interventions has been identified that can reduce the risk of MVV introduction and transmission. The factors associated with protection, as identified in several epidemiological studies, point to a clear set of best practices. Vieira et al. [8] conducted a study in Paraná, Brazil, and found that conducting a defined breeding season, supplying concentrated feed, and separating the breeding stock before birth were factors associated with protection, whereas keeping cats close to the flock, breeding on pasture, and previous problems with lice were associated with increased risk. These findings suggest that overall herd technification, the degree to which management is structured and sanitary practices are implemented, is inversely associated with MVV seropositivity. The protective effect of a defined breeding season likely reflects the ability to manage lambing cohorts and reduce prolonged close contact between ewes and lambs, while the availability of concentrate feed may improve body condition and immune competence.

The role of colostrum and milk in transmission deserves particular attention. While the study by Illius et al. [13] downplayed the importance of maternal transmission, other research has demonstrated that MVV can be detected in milk and colostrum, and that ingestion by lambs is a potential route of infection [23, 50]. Gayo et al. [23] used immunocytochemistry to detect MVV in macrophages from milk samples of 16 out of 39 infected sheep, confirming viral excretion in milk. However, the authors noted that positivity was found only in macrophages, not in epithelial cells, and that viral detection in milk was primarily associated with moderate to severe mammary gland lesions. This suggests that while colostrum and milk can transmit MVV, the risk is highest in animals with active mammary inflammation, and that early removal of lambs from seropositive ewes and feeding of heat-treated colostrum or milk replacer can substantially reduce this risk. Many eradication programs, including the Norwegian scheme, mandate the feeding of pasteurized colostrum to lambs from infected ewes, and this practice is widely regarded as a critical component of control.

The risk of virus introduction through purchased animals is consistently identified as the single most important factor in flock outbreaks. The study by Frölich et al. [19] in Germany found that the purchase of ewes was the main environmental risk factor for seropositivity. Similarly, Yizengaw et al. [15] traced MVV introduction in Ethiopian flocks to the purchase of Awassi cross rams from a distributor farm. These findings underscore the necessity of quarantine and pre-movement testing for all introduced animals. The duration of quarantine should be sufficient to allow seroconversion in recently infected animals, and ideally should include molecular testing to detect proviral DNA in animals that have not yet seroconverted. The cost and logistical complexity of such measures, however, can be substantial, particularly for smallholder farmers.

Future Directions: Vaccine Development, Vif Biology, and Integrated Control

Given the intractability of MVV to conventional control, the development of an effective vaccine has been a long-standing goal. The challenges are formidable: lentiviruses are notorious for their ability to evade the immune response, establish latent reservoirs, and undergo rapid antigenic variation. The reverse vaccinology approach, which uses computational tools to identify epitopes that are antigenic, non-allergenic, non-toxic, and capable of eliciting a protective immune response, has been applied to MVV in silico [5]. Koçkaya et al. [5] constructed a multi-epitope vaccine candidate based on 19 epitopes from the Gag and Env proteins and demonstrated in silico a strong binding affinity to Toll-like receptors 2 and 4, suggesting that this construct could induce both innate and adaptive immunity. The Gag protein was identified as a superior vaccine antigen due to its higher conservation and antigenicity, as well as the absence of transmembrane helices that would complicate recombinant expression. While these in silico predictions are encouraging, the translation to a practical vaccine that protects against multiple circulating genotypes remains a distant prospect. The high genetic diversity of MVV, particularly in the Env protein, means that any vaccine would likely need to be multivalent or updated periodically to match circulating strains.

A more immediate and perhaps more achievable approach to reducing the impact of MVV is the development of antiviral strategies targeting the viral life cycle. The discovery that MVV Vif protein recruits cyclophilin A (CypA) as a non-canonical cofactor to recruit the Cullin-RING E3 ubiquitin ligase complex for the degradation of host APOBEC3 restriction factors has opened new avenues for therapeutic intervention [33, 36, 38]. The cryo-electron microscopy structure of MVV Vif in complex with CypA and the E3 ligase components, solved by Hu et al. [33], provides a detailed map of the protein-protein interfaces that could be targeted by small molecule inhibitors. Unlike HIV-1 Vif, which uses CBFβ as its cofactor, MVV Vif has evolved a unique mechanism that may be more amenable to inhibition because CypA is a well-characterized target for which existing drugs, such as cyclosporine A, are available. The zinc-binding motif in MVV Vif, while distinct from that of HIV-1 Vif, is also essential for function and represents another potential drug target [36]. Furthermore, the demonstration that MVV Vif induces G2/M cell cycle arrest through the degradation of B56 regulatory subunits of protein phosphatase 2A (PP2A) suggests that this accessory function is conserved across lentiviruses and may be required for optimal viral replication [34]. Interfering with Vif-mediated cell cycle arrest could attenuate viral pathogenesis. While these molecular insights have not yet translated into clinical applications, they provide a rational basis for the development of antiviral compounds that could be used to treat infected animals or reduce transmission.

The future of MVV control will likely involve an integrated approach that combines the best available tools: sensitive and regionally validated diagnostics, strategic test-and-cull informed by epidemiological modeling, management practices that minimize housing density and improve biosecurity, genetic selection for resistance alleles, and, eventually, prophylactic or therapeutic vaccines. The success of the Norwegian eradication program, which relies on a combination of voluntary participation, diagnostic testing using

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